Accumulation of mononuclear phagocytes (m?) at sites of ?-Amyloid (A?) deposition in the brain is a hallmark of Alzheimer's disease (AD) and related animal models. Our work indicates that resident microglia, and CCR2+ monocytes recruited from the blood are involved. These cells can be neuroprotective and promote A? clearance in part via the scavenger receptor Scara1, but their interaction with A? via a CD36/TLR4/TLR6 receptor complex activates the Nlrp3 inflammasome, they lose their phagocytic ability and produce neurotoxins and inflammatory cytokines that promote A? production and Tau phosphorylation (pTau), thereby contributing to neurodegeneration. GWAS studies provided added support for a key role for m? in AD pathogenesis in humans since mutations in the m? genes TREM2 and CD33 increase the risk for late onset AD. TREM2 and CD33 may regulate A? clearance in opposing manners via yet to- be-defined pathways. It is not known if TREM2 and CD33 regulate A?-induced changes in m? functions or gene expression. The distinct roles of microglia vs. monocytes in AD pathogenesis and how AD alters their transcriptomes, proteomes and functions are not established yet. To begin to address this problem, we defined the quantitative transcriptomes of microglia and monocytes by RNASeq. We found that aging changes the transcriptomes of microglia to assume a neuroprotective profile, while monocytes maintain their toxic/inflammatory abilities. The link(s) between how the innate immune system interacts with A? and regulates pTau and neurotoxicity, and how mutations in specific immune genes increase the risk for of AD remain unclear. In this application we propose to establish these links and determine whether TREM2 and CD33 regulate m? pathways relevant to AD pathogenesis such as A? clearance and generation, inflammasome activation, and pathways that lead to tau phosphorylation and neurotoxicity and at which disease stage and in what cell type are these pathways regulated.